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Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study
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Original article
Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study F. Labombarda a,∗, M. Leport b, R. Morello c, V. Ribault b, D. Kauffman b, J. Brouard b, A. Pellissier a, P. Maragnes a , A. Manrique d,e , P. Milliez a , E. Saloux a a
CHU de Caen, Department of Cardiology, avenue Côte-de-Nacre, 14033 Caen, France b CHU de Caen, Department of Pediatrics, 14033 Caen, France c CHU de Caen, Biostatistics and Clinical Research Unit, Université de Caen Basse-Normandie, Medical School, 14033 Caen, France d EA 4650, Université de Caen Basse-Normandie, 14033 Caen, France e CHU de Caen, GIP CYCERON, Department of imaging, 14033 Caen, France Received 6 January 2014; accepted 31 March 2014
Abstract Aim. – Type 1 diabetes (T1D) involves complex metabolic disturbances in cardiomyocytes leading to morphological and functional abnormalities of the myocardium. The relationship between T1D and cardiac structure and function in children is not well established. Our study investigated whether T1D is associated with early subclinical myocardial disturbances in children and adolescents, and whether the state of metabolic control and diabetes duration are influential factors. Methods. – Standard echocardiography, tissue Doppler imaging (TDI) and two-dimensional (2D) strain imaging were prospectively performed in 100 T1D children (age: 11.3 ± 3.6 years, 52 boys) and compared with 79 controls. Results. – The diabetic and control children were comparable with respect to age, gender, heart rate and blood pressure. There were no significant differences between the two groups in left ventricular (LV) ejection fraction, LV remodelling and TDI parameters. Conventional mitral Doppler demonstrated significantly fewer diastolic filling abnormalities with an early filling wave in the diabetes group. Global longitudinal strain (GLS) was also significantly lower in the T1D children, while circumferential strain and radial strain did not differ. GLS correlated with HbA1c (r = 0.52; P < 0.01), but there was no correlation with diabetes duration. Conclusion. – Our results suggest that LV longitudinal myocardial deformation is decreased in young patients with T1D, and glycaemic control may be the main risk factor for these changes. Further follow-up is now necessary to precisely determine the clinical significance of these myocardial changes detected by 2D strain imaging in T1D children. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Type 1 diabetes; Children; 2D strain; Echocardiography
1. Introduction
∗
Corresponding author. Tel.: +33 2 31 06 47 67; fax: +33 2 31 06 44 18. E-mail addresses: [email protected], [email protected] (F. Labombarda), [email protected] (M. Leport), [email protected] (R. Morello), [email protected] (V. Ribault), [email protected] (D. Kauffman), [email protected] (J. Brouard), [email protected] (A. Pellissier), [email protected] (P. Maragnes), [email protected] (A. Manrique), [email protected] (P. Milliez), [email protected] (E. Saloux).
Type 1 diabetes (T1D) is a major cardiovascular risk factor associated with excess mortality in young adults due to premature cardiovascular events [1], including heart failure [2]. T1D involves complex metabolic disturbances in cardiomyocytes leading to morphological and functional abnormalities of the myocardium [3]. The relationship between T1D and cardiac structure and function in children and adolescents is not well established. Most of the previous studies focused on diastolic function using standard two-dimensional (2D) and Doppler echocardiography, while the study of systolic function
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Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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was restricted to measurement of left ventricular ejection fraction (LVEF) [4,5]. 2D strain imaging is a recent echocardiographic method for the assessment of myocardial function. The left ventricular myocardium is a complex threedimensional structure consisting of myocardial fibres orientated in different directions and responsible for three principal types of deformation, or ‘strain’: global longitudinal strain (GLS); radial strain; and circumferential strain. 2D strain imaging is a robust echocardiographic technique that enables evaluation of the three components of myocardial deformation from a standard 2D view. 2D strain imaging has been shown to be the most sensitive echocardiographic tool for the detection of the subclinical impairment of myocardial function observed in many conditions predisposing to heart failure [6]. The present study used 2D strain imaging to investigate whether T1D children and adolescents show early abnormalities in myocardial function. In addition, the relationship between these myocardial features and glycaemic control and diabetes duration were investigated. 2. Methods 2.1. Population The study prospectively recruited diabetic patients aged 5 to 18 years followed-up at the paediatric department of the Caen teaching hospital. T1D was diagnosed according to World Health Organization criteria [7] together with the permanent need for insulin therapy. Exclusion criteria were the presence of cardiopathy, significant concomitant disease, medication known to modify cardiac function, high blood pressure, smoking, dyslipidaemia and obesity [defined as a body mass index (BMI), adjusted for gender and age, exceeding the 97th percentile according to French reference values] [8]. Not included were recently diagnosed (< 1 year) diabetic children. Diabetic patients were compared with healthy control children from our outpatients department of paediatric cardiology selected from children being investigated for physiological cardiac murmur whose echocardiography was normal. To be included in the control group, children had to have no personal antecedents or family history of either high blood pressure or hypercholesterolaemia. The study protocol was approved by the hospital ethics review board. Patients provided their informed consent through legal representatives. 2.2. Clinical evaluation Demographic details of age, gender, weight, height and heart rate were recorded. Their body surface area (BSA) was calculated according to the Dubois formula and expressed in m2 . BMI was calculated according to the formula of weight (kg) divided by height squared (m2 ). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured after 10 minutes at rest with a calibrated automatic blood pressure monitor (Datascope® DUO). For diabetic patients, diabetes duration (expressed in years) was considered for each individual based on the full-attained age on the first day of insulin therapy.
2.3. Biochemistry Fasting blood samples were taken from the diabetic children to analyze lipid balance [total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and low-density lipoprotein (LDL) cholesterol, calculated according to the Friedewald formula; Beckman Coulter DxC 800 system, cholesterol oxidase and cholesterol esterase method] and HbA1c . HbA1c was measured by high-performance liquid chromatography (Tosoh Corporation, Tokyo, Japan). This study used the mean quarterly HbA1c (mmol/mol, %) for the year prior to the study. 2.4. Echocardiography Every subject underwent a 2D echocardiography examination (iE33 system, S5 probe, Philips Healthcare, Best, The Netherlands), including the standard echocardiographic views, tissue Doppler imaging (TDI) and 2D strain analysis. 2.4.1. Conventional echocardiography and tissue Doppler imaging LVEF was assessed using the biplane Simpson’s method in apical view. Left ventricular end-diastolic dimension (LV-EDD), interventricular septal end-diastolic dimension (IVS-EDD) and left ventricular posterior wall end-diastolic dimension (LVPWEDD) were measured in time motion (TM) mode in parasternal long-axis view. Left ventricular mass (LVM) was calculated by the Devereux formula and indexed by height raised to the power of 2.7. The mitral Doppler signal was recorded in the apical four-chamber view, with the Doppler sample volume placed at the tip of the mitral valve. Peak velocities of early (E) and late (A) filling waves, early/late filling ratio of peak velocities (E/A) and mitral deceleration time (MDT) were measured on the basis of transmitral flow velocities. Left atrial volume (LAV) was measured from standard apical two- and four-chamber views at end-systole, using the biplane method, and indexed to BSA. Acquisitions in pulsed-wave TDI mode were made in apical four-chamber view. The sample volume was placed at the basal level of the right ventricular and left ventricular free walls to measure tricuspid peak systolic velocity (St) and early mitral peak diastolic velocity (Ea). 2.4.2. 2D strain analysis For this analysis, standard 2D grey-scale acquisitions were made in the short-axis parasternal view at the mitral papillary muscles and in the three standard apical chamber views. All images were recorded at a high image rate at > 50 Hz and stored for post-processing analysis with QLAB advanced quantification software (Philips). Using apical views, fast semi-automatic contouring of the endocardium was carried out by placing three points on the image (basal septum, basal lateral wall and apex) at the endocardium and epicardium. The software then suggested a region of interest of adjustable thickness that could be repositioned by the operator, but which had to correspond to the thickness of the wall to be analyzed. The operator ensured contouring and optimal tracking of the movements of each wall segment by the software. When myocardial tracking was considered optimal by the operator, the software analyzed the
Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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global and segmental strains and represented them as coloured curves. The strain peak corresponded to the mean of the strain peaks of each subregion. GLS was quantified from an apical view (supplementary material, Fig. S1). In the short-axis view, the software performed automatic circular contouring that the operator adjusted and positioned on the endocardium–chamber interface. Both circumferential and radial strains were obtained from a short-axis parasternal view (supplementary material, Fig. S1). Apnoea is required for 2D strain acquisition and our study limit was age 5 years as, in our experience, most children aged under 5 are unable to cooperate for apnoea. 2.5. Statistical methods Quantitative variables were described using means and standard deviations (SD), and qualitative variables were described using frequencies and percentages. Student’s t-test was used to compare the means of quantitative variables in two independent groups, and the chi-square test was used to estimate the relationship between qualitative variables. The ability of echocardiographic parameters to discriminate diabetic and healthy subjects was evaluated using receiver operating characteristic (ROC) curve analyses, and the area under the curve (AUC) indicated the discriminant value of the test. The relationship between two quantitative variables was assessed using Pearson’s correlation. Intra- and interobserver variability for strain measurements were assessed, using a coefficient of variation formula, from a randomly selected sample of 10 study children. All tests were two-tailed and their level of significance was defined as P < 0.05. IBM-SPSS 20.0 for Windows was the statistical software used. 3. Results 3.1. Study population Between January 2012 and January 2013, 100 children and adolescents with T1D (age: 11.3 ± 3.6 years, 52 boys) were consecutively recruited at our paediatric endocrinology department from a cohort of 152 diabetes patients. Reasons for non-inclusion were: age > 18 years (n = 10) or < 5 years (n = 9); diabetes duration < 1 year (n = 23); obesity (n = 7); and refusal to participate (n = 3). Diabetes duration ranged from 1.1 to 16 years (median: 5.1 ± 3.1 years). Results in the diabetes patients were compared with those in 79 healthy children recruited as a control group over the same time period. The diabetic and control children were comparable with respect to age, gender, heart rate, SBP, DBP and mean BP. The physical and biological characteristics of our study population are shown in Table 1. 3.2. Echocardiographic measurements 3.2.1. Conventional echocardiography and TDI There were no significant differences between the two study groups in LVEF, LV diameter, LAV index, wall thickness, standard diastolic function parameters (A wave, E/A ratio and mitral deceleration time) and TDI parameters (Table 2). The E wave
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Table 1 Physical and biological characteristics in type 1 diabetes and control children. Diabetic children Controls (n = 79) (n = 100)
P
Demographics Male Age (years) Weight (kg) Height (m) BSA (m2 ) BMI (kg/m2 ) BMI Z score Heart rate (bpm) SBP (mmHg) DBP (mmHg) MBP (mmHg) Duration diabetes (years)
52/100 (52%) 11.3 ± 3.6 41.1 ± 16.3 146.8 ± 20.9 1.30 ± 0.34 18.4 ± 2.9 0.32 ± 1.17 77.1 ± 12 110.2 ± 11.6 63 ± 10.4 78.1 ± 8.5 5.1 ± 3.1
42/79 (53%) 11.8 ± 3.2 40 ± 12.8 147.5 ± 17.8 1.27 ± 0.29 17.8 ± 2.1 −0.16 ± 0.73 76.3 ± 11.4 108.9 ± 10.9 62.9 ± 8.1 78.2 ± 8.4 –
0.877 0.308 0.611 0.805 0.56 0.087 0.001 0.65 0.45 0.97 0.94 –
Biology HbA1c [% (mmol/mol)] Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L)
8.4 (68 ± 1.47) 4.42 ± 0.73 2.29 ± 0.62 1.87 ± 0.59 0.8 ± 0.25
– – – – –
– – – – –
Values are presented as means ± SD. BSA: body surface area; BMI: body mass index; bpm: beats per minute; SBP/DBP/MBP: systolic/diastolic/mean blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein.
was significantly lower in the diabetes group (Table 2). Also, a bicuspid aortic valve without stenosis or regurgitation was incidentally diagnosed in two diabetic children. 3.2.2. 2D strain analysis In our control group, there were no significant gender or age differences in myocardial 2D strain values (supplementary material, Tables S1–S5), whereas GLS was significantly lower in the diabetes vs. control group (−17.6 ± 1.6% vs. −20.5 ± 1.4%, Table 2 Standard two-dimensional echocardiographic characteristics in diabetic and control children. Diabetic children (n = 100) LV-EDD (mm) IVS-EDD (mm) LVPW-EDD (mm) LVMI (g/m2.7 ) LVEF (%) E (cm/s) A (cm/s) E/A MDT (ms) Ea (cm/s) E/Ea LAVI (mL/m2 ) St (cm/s)
41.7 6.84 6.59 87.7 65.3 102.7 55.15 1.99 179.9 18.1 5.7 20.3 13.4
± ± ± ± ± ± ± ± ± ± ± ± ±
5.9 1.63 1.28 35.7 5.9 16 11.9 0.44 30.9 3.8 1.3 3.2 2.1
Controls (n = 79) 42.5 6.99 6.6 88.9 64.9 108.4 55.7 2 183.5 18.2 6.1 20.5 13.9
± ± ± ± ± ± ± ± ± ± ± ± ±
P 6.7 1.45 1.33 37.4 5.3 17.6 13.1 0.44 25.1 3.3 1.4 3.2 2.89
0.38 0.51 0.96 0.83 0.61 0.025 0.76 0.08 0.39 0.92 0.11 0.65 0.10
Values are presented as means ± SD. LV-EDD: left ventricular end-diastolic dimension; IVS-EDD: interventricular septal end-diastolic dimension; LVPWEDD: left ventricular posterior wall end-diastolic dimension; LVMI: left ventricular mass index; LVEF: left ventricular ejection fraction; E: mitral early peak velocity; A: mitral late peak velocity; MDT: mitral deceleration time; Ea: mitral annulus early peak velocity; LAVI: left atrial volume index; St: tricuspid peak systolic velocity.
Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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Fig. 1. Comparison of radial strain (lower), circumferential strain (middle) and global longitudinal strain (upper) between diabetic and control children.
respectively; P < 0.001), although circumferential strain and radial strain did not differ (Fig. 1). Also, 7.6% of segments were excluded from the strain calculation because of inadequate tracking. The diagnostic performance of GLS and E wave, and the proposed cutoff values, is presented as ROC curves on Fig. 2. Unlike GLS, the E wave failed to discriminate between the diabetes and control groups. 3.3. Relationship between HbA1c and clinical, biological and echocardiographic (GLS and E wave) parameters No correlation was found between HbA1c and BMI, SBP, DBP, mean BP and lipid balance (supplementary material, Tables S1–S5). While GLS was significantly correlated with HbA1c (r = 0.52; P < 0.01; Fig. 3), there was no correlation with diabetes duration (r = 0.14; P = 0.28). Diabetic patients were divided into three groups according to their tertile of HbA1c level (< 7.8%, 7.8–8.7% and > 8.7%). GLS was significantly lower in patients with HbA1c > 8.7% compared with the two other tertiles (Fig. 3). No correlation was found between E wave and either HbA1c (r = −0.54; P = 0.59) or diabetes duration (r = 0.13; P = 0.17). 3.4. Reproducibility Intraobserver reproducibility was 5% for GLS, 7% for circumferential strain and 11% for radial strain. Interobserver reproducibility was 8% for GLS, 9% for circumferential strain and 13% for radial strain.
4. Discussion Our study suggests that diabetes in childhood is associated with alteration of longitudinal LV deformation. These myocardial deformation changes appear to be related to glycaemic control. Previous echocardiographic studies in diabetic children focused on LV diastolic function and suggested a reduction in early diastolic filling based on transmitral flow analysis [4,5,9,10]. On evaluating LVEF, all previous studies conducted in diabetic children concluded the absence of LV systolic dysfunction. Because of cardiac geometry and myofibre arrangements, LV function goes through complex myocardial deformations, or ‘strains’, and cannot be reduced to a simple variation of volume, as with assessment of LVEF. GLS of the left ventricle plays an important role in cardiac pump function; it is primarily controlled by subendocardial longitudinal myofibres, which are more susceptible to ischaemia and fibrosis [11]. This explains why subclinical impairment in GLS represents the first anomaly observed in the setting of many conditions predisposing to heart failure, such as hypertension [12]. Our results agree with studies of Fang et al. [13] and Shivu et al. [14], who reported decreases of longitudinal strain in the left ventricle of adult T1D patients. However, these reports are difficult to interpret because they included adult patients, in whom the influence of comorbidities such as age, hypertension and coronary heart disease could not be excluded. Such comorbidities may be considered non-existent in our cohort of diabetic children, who represent a unique model in which to investigate the early effects of metabolic disturbances induced by T1D on myocardial function. In our present study, the decreased GLS was observed
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Fig. 2. Receiver operating characteristic curves for global longitudinal strain (left) and E wave (right). AUC: area under the curve.
while LVM and cardiac dimensions were comparable between diabetics and controls, a result consistent with experimental T1D animal studies, which reported diastolic and systolic dysfunction in the absence of cardiomyocyte hypertrophy [3]. Functional myocardial changes are induced by various complex mechanisms in which chronic hyperglycaemia evidently plays a pathophysiological role [3,15]. Our results agree with those of several studies demonstrating a relationship between glycaemic control and cardiac function or heart failure in diabetic children [16], adults [17] and animals [18]. In the same way, a higher mean HbA1c was significantly associated with alterations in LV structure and function, and with myocardial scars in patients with T1D [19]. An independent role of glycaemic control in the pathogenesis of heart failure has also been demonstrated [2].
We could find no correlation between diabetes duration and decreased GLS. Indeed, the impact of diabetes duration on myocardial function remains a subject of debate. An association between diabetes duration and decreased GLS was reported in adults with a longer mean diabetes duration than in our present study [20]. Nevertheless, no deleterious effects of diabetes duration on myocardial function have been evidenced in diabetic children [4,17], adults [21] or experimental diabetic rats [18]. Diabetes generates lesions that remain silent during childhood, but are expressed in adulthood by excess cardiovascular mortality mainly attributed to coronary artery disease and heart failure. In childhood, T1D is associated with early endothelial dysfunction and increased arterial stiffness, both established markers of coronary artery atherosclerosis [22]. Similarly, our results suggest that T1D may be associated
Fig. 3. Relationship between global longitudinal strain (%; GLS) and HbA1c (%). A. correlation between HbA1c (%) and GLS (%). B. Comparison of GLS in diabetic patients according to tertile of HbA1c level (< 7.8%, 7.8–8.7% and > 8.7%).
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with early longitudinal strain impairment that may be the first marker of preclinical diabetic cardiomyopathy, as previously suggested in type 2 diabetes [23,24]. Further studies are now required to determine the prognostic value of these subclinical abnormalities of cardiac function in diabetic children. In our present study, metabolic blood tests were not performed in the healthy controls. Also, no attempt was made to correlate myocardial strain parameters with oxidative stress and inflammation markers known to contribute to myocardial dysfunction in various cardiometabolic diseases. Finally, as a cross-sectional study, the natural history of the development and progression of altered longitudinal deformation was unknown. It is also not known whether strict glycaemic control might be associated with improvement of GLS. 5. Conclusion Our study has suggested that LV longitudinal function is impaired in young patients with T1D, and glycaemic control may be the main risk factor for the myocardial changes. Further follow-up is now necessary to precisely elucidate the clinical significance of the myocardial changes detected by 2D strain imaging in T1D children. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements and author’s contributions All authors contributed significantly to this work (FL researched data and wrote the manuscript; FL, AP, ES performed the echocardiograms; ML and VR researched data), contributed to the discussion and reviewed the manuscript. ES, PM, DK, PM, AM and JB critically revised the manuscript. RM did the statistical analysis. FL is the guarantor of this work and, as such, had full access to all the data in the study, and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors have read and approved the final version of the manuscript. Funding: None.
Appendix A. Supplementary material Supplementary materials (Fig. S1, Tables S1–S5 and French abstract) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.diabet.2014.03.007. References [1] Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, et al. The British Diabetic Association Cohort Study, II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet Med 1999;16:466–71.
[2] Lind M, Bounias I, Olsson M, Gudbjörnsdottir S, Svensson AM, Rosengren A. Control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet 2011;378:140–6. [3] Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 2006;98:596–605. [4] Suys B, Katier B, Rooman R, Matthys D, Op De Beeck L, Du Caju MV, et al. Female children and adolescents with type 1 diabetes have more pronounced early echocardiographic signs of diabetic cardiomyopathy. Diabetes Care 2004;27:1947–53. [5] Gunczler P, Lanes R, Lopez E, Esaa S, Villarroel O, Revel-Chion R. Cardiac mass and function, carotid artery intima-media thickness and lipoprotein (a) levels in children and adolescents with type 1 diabetes mellitus of short duration. J Pediatr Endocrinol Metab 2002;15:181–6. [6] Geyer H, Caracciolo G, Abe H, Wilansky S, Carerj S, Gentile F, et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010;23:351–69. [7] World Health Organization Expert Committee on Diabetes Mellitus. Second report, technical report series. Geneva: WHO; 1980. [8] Rolland-Cachera MF, Cole TJ, Sempé M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Am J Clin Nutr 1991;45:13–21. [9] Riggs TW, Transue D. Doppler echocardiographic evaluation of left ventricular diastolic function in adolescents with diabetes mellitus. Am J Cardiol 1990;65:899–902. [10] Salem M, El Behery S, Adly A, Khalil D, El Hadidi E. Early predictors of myocardial disease in children and adolescents with type 1 diabetes mellitus. Pediatric Diabetes 2009;10:513–21. [11] Lumens J, Delhaas T, Arts T, Cowan BR, Young AA. Impaired subendocardial contractile myofiber function in asymptomatic aged humans, as detected using MRI. Am J Physiol Heart Circ Physiol 2006;291: 1573–9. [12] Shah AM, Solomon SD. Myocardial deformation imaging: current status and future directions. Circulation 2012;125:e244–8. [13] Fang ZY, Leano R, Marwick TH. Relationship between longitudinal and radial contractility in subclinical diabetic heart disease. Clin Sci (Lond) 2004;106:53–60. [14] Shivu GN, Abozquia K, Phan TT, Narendran P, Stevens M, Frenneaux M. Increased left ventricular torsion in uncomplicated type 1 diabetic patients: the role of coronary microvascular function. Diabetes Care 2009:321710–2. [15] Rajesh M, Bátkai S, Kechrid M, Mukhopadhyay P, Lee WS, Horváth B, et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 2012;61:716–27. [16] Kim EH, Kim YH. Left ventricular function in children and adolescents with type 1 diabetes mellitus. Korean Circ J 2010;40:125–30. [17] Chung J, Abraszewski P, Yu X, Liu W, Krainik AJ, Ashford M, et al. Paradoxical increase in ventricular torsion and systolic torsion rate in type I diabetic patients under tight glycaemic control. J Am Coll Cardiol 2006;47:384–90. [18] Kita Y, Shimizu M, Sugihara N, Shimizu K, Yoshio H, Shibayama S, et al. Correlation between histopathological changes and mechanical dysfunction in diabetic rat hearts. Diabetes Res Clin Pract 1991;11: 177–88. [19] Turkbey EB, Backlund JY, Genuth S, Jain A, Miao C, Cleary PA, et al. Myocardial structure, function, and scar in patients with type 1 diabetes mellitus. Circulation 2011;124:1737–46. [20] Nakai H, Takeuchi M, Nishikage T, Lang RM, Otsuji Y. Subclinical left ventricular dysfunction in asymptomatic diabetic patients assessed by twodimensional speckle tracking echocardiography: correlation with diabetic duration. Eur J Echocardiogr 2009;10:926–32. [21] Karamitsos TD, Karvounis HI, Dalamanga EG, Papadopoulos CE, Didangellos TP, Karamitsos DT, et al. Early diastolic impairment of diabetic heart: the significance of right ventricle. Int J Cardiol 2007;114: 218–23. [22] Järvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004;109:1750–5.
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[23] Ernande L, Bergerot C, Rietzschel ER, De Buyzere ML, Thibault H, Pignonblanc PG, et al. Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 2011;24:1268–75.
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[24] Andersson C, Gislason GH, Weeke P, Hoffmann S, Hansen PR, TorpPedersen C, et al. Diabetes is associated with impaired myocardial performance in patients without significant coronary artery disease. Cardiovasc Diabetol 2010;9:3.
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Original article
Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study F. Labombarda a,∗, M. Leport b, R. Morello c, V. Ribault b, D. Kauffman b, J. Brouard b, A. Pellissier a, P. Maragnes a , A. Manrique d,e , P. Milliez a , E. Saloux a a
CHU de Caen, Department of Cardiology, avenue Côte-de-Nacre, 14033 Caen, France b CHU de Caen, Department of Pediatrics, 14033 Caen, France c CHU de Caen, Biostatistics and Clinical Research Unit, Université de Caen Basse-Normandie, Medical School, 14033 Caen, France d EA 4650, Université de Caen Basse-Normandie, 14033 Caen, France e CHU de Caen, GIP CYCERON, Department of imaging, 14033 Caen, France Received 6 January 2014; accepted 31 March 2014
Abstract Aim. – Type 1 diabetes (T1D) involves complex metabolic disturbances in cardiomyocytes leading to morphological and functional abnormalities of the myocardium. The relationship between T1D and cardiac structure and function in children is not well established. Our study investigated whether T1D is associated with early subclinical myocardial disturbances in children and adolescents, and whether the state of metabolic control and diabetes duration are influential factors. Methods. – Standard echocardiography, tissue Doppler imaging (TDI) and two-dimensional (2D) strain imaging were prospectively performed in 100 T1D children (age: 11.3 ± 3.6 years, 52 boys) and compared with 79 controls. Results. – The diabetic and control children were comparable with respect to age, gender, heart rate and blood pressure. There were no significant differences between the two groups in left ventricular (LV) ejection fraction, LV remodelling and TDI parameters. Conventional mitral Doppler demonstrated significantly fewer diastolic filling abnormalities with an early filling wave in the diabetes group. Global longitudinal strain (GLS) was also significantly lower in the T1D children, while circumferential strain and radial strain did not differ. GLS correlated with HbA1c (r = 0.52; P < 0.01), but there was no correlation with diabetes duration. Conclusion. – Our results suggest that LV longitudinal myocardial deformation is decreased in young patients with T1D, and glycaemic control may be the main risk factor for these changes. Further follow-up is now necessary to precisely determine the clinical significance of these myocardial changes detected by 2D strain imaging in T1D children. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Type 1 diabetes; Children; 2D strain; Echocardiography
1. Introduction
∗
Corresponding author. Tel.: +33 2 31 06 47 67; fax: +33 2 31 06 44 18. E-mail addresses: [email protected], [email protected] (F. Labombarda), [email protected] (M. Leport), [email protected] (R. Morello), [email protected] (V. Ribault), [email protected] (D. Kauffman), [email protected] (J. Brouard), [email protected] (A. Pellissier), [email protected] (P. Maragnes), [email protected] (A. Manrique), [email protected] (P. Milliez), [email protected] (E. Saloux).
Type 1 diabetes (T1D) is a major cardiovascular risk factor associated with excess mortality in young adults due to premature cardiovascular events [1], including heart failure [2]. T1D involves complex metabolic disturbances in cardiomyocytes leading to morphological and functional abnormalities of the myocardium [3]. The relationship between T1D and cardiac structure and function in children and adolescents is not well established. Most of the previous studies focused on diastolic function using standard two-dimensional (2D) and Doppler echocardiography, while the study of systolic function
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Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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was restricted to measurement of left ventricular ejection fraction (LVEF) [4,5]. 2D strain imaging is a recent echocardiographic method for the assessment of myocardial function. The left ventricular myocardium is a complex threedimensional structure consisting of myocardial fibres orientated in different directions and responsible for three principal types of deformation, or ‘strain’: global longitudinal strain (GLS); radial strain; and circumferential strain. 2D strain imaging is a robust echocardiographic technique that enables evaluation of the three components of myocardial deformation from a standard 2D view. 2D strain imaging has been shown to be the most sensitive echocardiographic tool for the detection of the subclinical impairment of myocardial function observed in many conditions predisposing to heart failure [6]. The present study used 2D strain imaging to investigate whether T1D children and adolescents show early abnormalities in myocardial function. In addition, the relationship between these myocardial features and glycaemic control and diabetes duration were investigated. 2. Methods 2.1. Population The study prospectively recruited diabetic patients aged 5 to 18 years followed-up at the paediatric department of the Caen teaching hospital. T1D was diagnosed according to World Health Organization criteria [7] together with the permanent need for insulin therapy. Exclusion criteria were the presence of cardiopathy, significant concomitant disease, medication known to modify cardiac function, high blood pressure, smoking, dyslipidaemia and obesity [defined as a body mass index (BMI), adjusted for gender and age, exceeding the 97th percentile according to French reference values] [8]. Not included were recently diagnosed (< 1 year) diabetic children. Diabetic patients were compared with healthy control children from our outpatients department of paediatric cardiology selected from children being investigated for physiological cardiac murmur whose echocardiography was normal. To be included in the control group, children had to have no personal antecedents or family history of either high blood pressure or hypercholesterolaemia. The study protocol was approved by the hospital ethics review board. Patients provided their informed consent through legal representatives. 2.2. Clinical evaluation Demographic details of age, gender, weight, height and heart rate were recorded. Their body surface area (BSA) was calculated according to the Dubois formula and expressed in m2 . BMI was calculated according to the formula of weight (kg) divided by height squared (m2 ). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured after 10 minutes at rest with a calibrated automatic blood pressure monitor (Datascope® DUO). For diabetic patients, diabetes duration (expressed in years) was considered for each individual based on the full-attained age on the first day of insulin therapy.
2.3. Biochemistry Fasting blood samples were taken from the diabetic children to analyze lipid balance [total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and low-density lipoprotein (LDL) cholesterol, calculated according to the Friedewald formula; Beckman Coulter DxC 800 system, cholesterol oxidase and cholesterol esterase method] and HbA1c . HbA1c was measured by high-performance liquid chromatography (Tosoh Corporation, Tokyo, Japan). This study used the mean quarterly HbA1c (mmol/mol, %) for the year prior to the study. 2.4. Echocardiography Every subject underwent a 2D echocardiography examination (iE33 system, S5 probe, Philips Healthcare, Best, The Netherlands), including the standard echocardiographic views, tissue Doppler imaging (TDI) and 2D strain analysis. 2.4.1. Conventional echocardiography and tissue Doppler imaging LVEF was assessed using the biplane Simpson’s method in apical view. Left ventricular end-diastolic dimension (LV-EDD), interventricular septal end-diastolic dimension (IVS-EDD) and left ventricular posterior wall end-diastolic dimension (LVPWEDD) were measured in time motion (TM) mode in parasternal long-axis view. Left ventricular mass (LVM) was calculated by the Devereux formula and indexed by height raised to the power of 2.7. The mitral Doppler signal was recorded in the apical four-chamber view, with the Doppler sample volume placed at the tip of the mitral valve. Peak velocities of early (E) and late (A) filling waves, early/late filling ratio of peak velocities (E/A) and mitral deceleration time (MDT) were measured on the basis of transmitral flow velocities. Left atrial volume (LAV) was measured from standard apical two- and four-chamber views at end-systole, using the biplane method, and indexed to BSA. Acquisitions in pulsed-wave TDI mode were made in apical four-chamber view. The sample volume was placed at the basal level of the right ventricular and left ventricular free walls to measure tricuspid peak systolic velocity (St) and early mitral peak diastolic velocity (Ea). 2.4.2. 2D strain analysis For this analysis, standard 2D grey-scale acquisitions were made in the short-axis parasternal view at the mitral papillary muscles and in the three standard apical chamber views. All images were recorded at a high image rate at > 50 Hz and stored for post-processing analysis with QLAB advanced quantification software (Philips). Using apical views, fast semi-automatic contouring of the endocardium was carried out by placing three points on the image (basal septum, basal lateral wall and apex) at the endocardium and epicardium. The software then suggested a region of interest of adjustable thickness that could be repositioned by the operator, but which had to correspond to the thickness of the wall to be analyzed. The operator ensured contouring and optimal tracking of the movements of each wall segment by the software. When myocardial tracking was considered optimal by the operator, the software analyzed the
Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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global and segmental strains and represented them as coloured curves. The strain peak corresponded to the mean of the strain peaks of each subregion. GLS was quantified from an apical view (supplementary material, Fig. S1). In the short-axis view, the software performed automatic circular contouring that the operator adjusted and positioned on the endocardium–chamber interface. Both circumferential and radial strains were obtained from a short-axis parasternal view (supplementary material, Fig. S1). Apnoea is required for 2D strain acquisition and our study limit was age 5 years as, in our experience, most children aged under 5 are unable to cooperate for apnoea. 2.5. Statistical methods Quantitative variables were described using means and standard deviations (SD), and qualitative variables were described using frequencies and percentages. Student’s t-test was used to compare the means of quantitative variables in two independent groups, and the chi-square test was used to estimate the relationship between qualitative variables. The ability of echocardiographic parameters to discriminate diabetic and healthy subjects was evaluated using receiver operating characteristic (ROC) curve analyses, and the area under the curve (AUC) indicated the discriminant value of the test. The relationship between two quantitative variables was assessed using Pearson’s correlation. Intra- and interobserver variability for strain measurements were assessed, using a coefficient of variation formula, from a randomly selected sample of 10 study children. All tests were two-tailed and their level of significance was defined as P < 0.05. IBM-SPSS 20.0 for Windows was the statistical software used. 3. Results 3.1. Study population Between January 2012 and January 2013, 100 children and adolescents with T1D (age: 11.3 ± 3.6 years, 52 boys) were consecutively recruited at our paediatric endocrinology department from a cohort of 152 diabetes patients. Reasons for non-inclusion were: age > 18 years (n = 10) or < 5 years (n = 9); diabetes duration < 1 year (n = 23); obesity (n = 7); and refusal to participate (n = 3). Diabetes duration ranged from 1.1 to 16 years (median: 5.1 ± 3.1 years). Results in the diabetes patients were compared with those in 79 healthy children recruited as a control group over the same time period. The diabetic and control children were comparable with respect to age, gender, heart rate, SBP, DBP and mean BP. The physical and biological characteristics of our study population are shown in Table 1. 3.2. Echocardiographic measurements 3.2.1. Conventional echocardiography and TDI There were no significant differences between the two study groups in LVEF, LV diameter, LAV index, wall thickness, standard diastolic function parameters (A wave, E/A ratio and mitral deceleration time) and TDI parameters (Table 2). The E wave
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Table 1 Physical and biological characteristics in type 1 diabetes and control children. Diabetic children Controls (n = 79) (n = 100)
P
Demographics Male Age (years) Weight (kg) Height (m) BSA (m2 ) BMI (kg/m2 ) BMI Z score Heart rate (bpm) SBP (mmHg) DBP (mmHg) MBP (mmHg) Duration diabetes (years)
52/100 (52%) 11.3 ± 3.6 41.1 ± 16.3 146.8 ± 20.9 1.30 ± 0.34 18.4 ± 2.9 0.32 ± 1.17 77.1 ± 12 110.2 ± 11.6 63 ± 10.4 78.1 ± 8.5 5.1 ± 3.1
42/79 (53%) 11.8 ± 3.2 40 ± 12.8 147.5 ± 17.8 1.27 ± 0.29 17.8 ± 2.1 −0.16 ± 0.73 76.3 ± 11.4 108.9 ± 10.9 62.9 ± 8.1 78.2 ± 8.4 –
0.877 0.308 0.611 0.805 0.56 0.087 0.001 0.65 0.45 0.97 0.94 –
Biology HbA1c [% (mmol/mol)] Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L)
8.4 (68 ± 1.47) 4.42 ± 0.73 2.29 ± 0.62 1.87 ± 0.59 0.8 ± 0.25
– – – – –
– – – – –
Values are presented as means ± SD. BSA: body surface area; BMI: body mass index; bpm: beats per minute; SBP/DBP/MBP: systolic/diastolic/mean blood pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein.
was significantly lower in the diabetes group (Table 2). Also, a bicuspid aortic valve without stenosis or regurgitation was incidentally diagnosed in two diabetic children. 3.2.2. 2D strain analysis In our control group, there were no significant gender or age differences in myocardial 2D strain values (supplementary material, Tables S1–S5), whereas GLS was significantly lower in the diabetes vs. control group (−17.6 ± 1.6% vs. −20.5 ± 1.4%, Table 2 Standard two-dimensional echocardiographic characteristics in diabetic and control children. Diabetic children (n = 100) LV-EDD (mm) IVS-EDD (mm) LVPW-EDD (mm) LVMI (g/m2.7 ) LVEF (%) E (cm/s) A (cm/s) E/A MDT (ms) Ea (cm/s) E/Ea LAVI (mL/m2 ) St (cm/s)
41.7 6.84 6.59 87.7 65.3 102.7 55.15 1.99 179.9 18.1 5.7 20.3 13.4
± ± ± ± ± ± ± ± ± ± ± ± ±
5.9 1.63 1.28 35.7 5.9 16 11.9 0.44 30.9 3.8 1.3 3.2 2.1
Controls (n = 79) 42.5 6.99 6.6 88.9 64.9 108.4 55.7 2 183.5 18.2 6.1 20.5 13.9
± ± ± ± ± ± ± ± ± ± ± ± ±
P 6.7 1.45 1.33 37.4 5.3 17.6 13.1 0.44 25.1 3.3 1.4 3.2 2.89
0.38 0.51 0.96 0.83 0.61 0.025 0.76 0.08 0.39 0.92 0.11 0.65 0.10
Values are presented as means ± SD. LV-EDD: left ventricular end-diastolic dimension; IVS-EDD: interventricular septal end-diastolic dimension; LVPWEDD: left ventricular posterior wall end-diastolic dimension; LVMI: left ventricular mass index; LVEF: left ventricular ejection fraction; E: mitral early peak velocity; A: mitral late peak velocity; MDT: mitral deceleration time; Ea: mitral annulus early peak velocity; LAVI: left atrial volume index; St: tricuspid peak systolic velocity.
Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007
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Fig. 1. Comparison of radial strain (lower), circumferential strain (middle) and global longitudinal strain (upper) between diabetic and control children.
respectively; P < 0.001), although circumferential strain and radial strain did not differ (Fig. 1). Also, 7.6% of segments were excluded from the strain calculation because of inadequate tracking. The diagnostic performance of GLS and E wave, and the proposed cutoff values, is presented as ROC curves on Fig. 2. Unlike GLS, the E wave failed to discriminate between the diabetes and control groups. 3.3. Relationship between HbA1c and clinical, biological and echocardiographic (GLS and E wave) parameters No correlation was found between HbA1c and BMI, SBP, DBP, mean BP and lipid balance (supplementary material, Tables S1–S5). While GLS was significantly correlated with HbA1c (r = 0.52; P < 0.01; Fig. 3), there was no correlation with diabetes duration (r = 0.14; P = 0.28). Diabetic patients were divided into three groups according to their tertile of HbA1c level (< 7.8%, 7.8–8.7% and > 8.7%). GLS was significantly lower in patients with HbA1c > 8.7% compared with the two other tertiles (Fig. 3). No correlation was found between E wave and either HbA1c (r = −0.54; P = 0.59) or diabetes duration (r = 0.13; P = 0.17). 3.4. Reproducibility Intraobserver reproducibility was 5% for GLS, 7% for circumferential strain and 11% for radial strain. Interobserver reproducibility was 8% for GLS, 9% for circumferential strain and 13% for radial strain.
4. Discussion Our study suggests that diabetes in childhood is associated with alteration of longitudinal LV deformation. These myocardial deformation changes appear to be related to glycaemic control. Previous echocardiographic studies in diabetic children focused on LV diastolic function and suggested a reduction in early diastolic filling based on transmitral flow analysis [4,5,9,10]. On evaluating LVEF, all previous studies conducted in diabetic children concluded the absence of LV systolic dysfunction. Because of cardiac geometry and myofibre arrangements, LV function goes through complex myocardial deformations, or ‘strains’, and cannot be reduced to a simple variation of volume, as with assessment of LVEF. GLS of the left ventricle plays an important role in cardiac pump function; it is primarily controlled by subendocardial longitudinal myofibres, which are more susceptible to ischaemia and fibrosis [11]. This explains why subclinical impairment in GLS represents the first anomaly observed in the setting of many conditions predisposing to heart failure, such as hypertension [12]. Our results agree with studies of Fang et al. [13] and Shivu et al. [14], who reported decreases of longitudinal strain in the left ventricle of adult T1D patients. However, these reports are difficult to interpret because they included adult patients, in whom the influence of comorbidities such as age, hypertension and coronary heart disease could not be excluded. Such comorbidities may be considered non-existent in our cohort of diabetic children, who represent a unique model in which to investigate the early effects of metabolic disturbances induced by T1D on myocardial function. In our present study, the decreased GLS was observed
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Fig. 2. Receiver operating characteristic curves for global longitudinal strain (left) and E wave (right). AUC: area under the curve.
while LVM and cardiac dimensions were comparable between diabetics and controls, a result consistent with experimental T1D animal studies, which reported diastolic and systolic dysfunction in the absence of cardiomyocyte hypertrophy [3]. Functional myocardial changes are induced by various complex mechanisms in which chronic hyperglycaemia evidently plays a pathophysiological role [3,15]. Our results agree with those of several studies demonstrating a relationship between glycaemic control and cardiac function or heart failure in diabetic children [16], adults [17] and animals [18]. In the same way, a higher mean HbA1c was significantly associated with alterations in LV structure and function, and with myocardial scars in patients with T1D [19]. An independent role of glycaemic control in the pathogenesis of heart failure has also been demonstrated [2].
We could find no correlation between diabetes duration and decreased GLS. Indeed, the impact of diabetes duration on myocardial function remains a subject of debate. An association between diabetes duration and decreased GLS was reported in adults with a longer mean diabetes duration than in our present study [20]. Nevertheless, no deleterious effects of diabetes duration on myocardial function have been evidenced in diabetic children [4,17], adults [21] or experimental diabetic rats [18]. Diabetes generates lesions that remain silent during childhood, but are expressed in adulthood by excess cardiovascular mortality mainly attributed to coronary artery disease and heart failure. In childhood, T1D is associated with early endothelial dysfunction and increased arterial stiffness, both established markers of coronary artery atherosclerosis [22]. Similarly, our results suggest that T1D may be associated
Fig. 3. Relationship between global longitudinal strain (%; GLS) and HbA1c (%). A. correlation between HbA1c (%) and GLS (%). B. Comparison of GLS in diabetic patients according to tertile of HbA1c level (< 7.8%, 7.8–8.7% and > 8.7%).
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with early longitudinal strain impairment that may be the first marker of preclinical diabetic cardiomyopathy, as previously suggested in type 2 diabetes [23,24]. Further studies are now required to determine the prognostic value of these subclinical abnormalities of cardiac function in diabetic children. In our present study, metabolic blood tests were not performed in the healthy controls. Also, no attempt was made to correlate myocardial strain parameters with oxidative stress and inflammation markers known to contribute to myocardial dysfunction in various cardiometabolic diseases. Finally, as a cross-sectional study, the natural history of the development and progression of altered longitudinal deformation was unknown. It is also not known whether strict glycaemic control might be associated with improvement of GLS. 5. Conclusion Our study has suggested that LV longitudinal function is impaired in young patients with T1D, and glycaemic control may be the main risk factor for the myocardial changes. Further follow-up is now necessary to precisely elucidate the clinical significance of the myocardial changes detected by 2D strain imaging in T1D children. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements and author’s contributions All authors contributed significantly to this work (FL researched data and wrote the manuscript; FL, AP, ES performed the echocardiograms; ML and VR researched data), contributed to the discussion and reviewed the manuscript. ES, PM, DK, PM, AM and JB critically revised the manuscript. RM did the statistical analysis. FL is the guarantor of this work and, as such, had full access to all the data in the study, and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors have read and approved the final version of the manuscript. Funding: None.
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Please cite this article in press as: Labombarda F, et al. Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: A 2D speckle strain imaging study. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2014.03.007